Stroke by blockage of cerebral artery supplying blood to the brain is a major cause of death and disability worldwide. Stroke in mammals, including in humans, often presents clinically as a disruption of blood flow to the brain and other parts of the neurological system. Mechanistically, this disruption of blood flow often results in ischemia, which can produce damage, death, and/or other injury to the tissue or organ with comprised blood flow. The etiology of ischemic injury is sometimes mediated at the molecular level.
Despite its public heath significance, treatment of ischemic stroke is limited to thrombolysis by tissue plasminogen activator administered intravenously within three hours of symptom onset. Only a small percentage (<5%) of stroke patients ultimately receive this treatment.
Calpain is a cysteine protease located in the cytosol of all cells, including neurons, and is implicated in cell death as part of the calcium modulated cascade of enzymatic events after ischemic damage. Dysregulation of calpain, a prominent cysteine proteinase recognized to play an important role in signal transduction, cell migration and regulation of apoptosis, has been implicated in a variety of neurodegenerative disorders, including tissue damage, following stroke, traumatic brain and spine injury. It has also been linked to pathogenesis of a variety of neurological diseases, such as multiple sclerosis, and Alzheimer's, Huntington's and Parkinson's disease. These disorders are characterized by intracellular calcium overload leading to excessive activation of calpains. In vivo inhibition of calpain using cysteine protease inhibitors (e.g. peptide aldehydes, alpha-keto esters and amides) diminishes the extent of neuronal damage following ischemia; however, none of these inhibitors is specific for calpain, since they also effectively inhibit other cysteine proteases as well.
Treatments for neurodegenerative diseases and brain pathologies remain limited. Previous calpain inhibitors have been studied as a potential treatment strategy for stroke, but these inhibitors are not selective for calpain and may incur unwanted side effects by their interaction with other proteases. Thus, an unmet need remains for methods, systems, and compositions for selectively inhibition of calpain and without unwanted side effects.